Mitochondrial permeability transition pore is a potential drug target for neurodegeneration

• Published in: Biochimica et biophysica acta 2014-08, Vol.1842 (8), p.1267-1272
• Main Authors: Rao, Valasani Koteswara, Carlson, Emily A., Yan, Shirley Shidu
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Amyloid β; Animals; Cyclophilin D; Cyclophilins - antagonists & inhibitors; Cyclophilins - metabolism; Humans; Ischemia - metabolism; Ischemia - pathology; Mitochondrial Membrane Transport Proteins - antagonists & inhibitors; Mitochondrial Membrane Transport Proteins - metabolism; Mitochondrial Permeability Transition Pore; Models, Biological; Molecular Targeted Therapy; Nerve Degeneration - drug therapy; Neurodegeneration; Peptidyl-Prolyl Isomerase F
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2013.09.003

Mitochondrial permeability transition pore (mPTP) plays a central role in alterations of mitochondrial structure and function leading to neuronal injury relevant to aging and neurodegenerative diseases including Alzheimer's disease (AD). mPTP putatively consists of the voltage-dependent anion channel (VDAC), the adenine nucleotide translocator (ANT) and cyclophilin D (CypD). Reactive oxygen species (ROS) increase intra-cellular calcium and enhance the formation of mPTP that leads to neuronal cell death in AD. CypD-dependent mPTP can play a crucial role in ischemia/reperfusion injury. The interaction of amyloid beta peptide (Aβ) with CypD potentiates mitochondrial and neuronal perturbation. This interaction triggers the formation of mPTP, resulting in decreased mitochondrial membrane potential, impaired mitochondrial respiration function, increased oxidative stress, release of cytochrome c, and impaired axonal mitochondrial transport. Thus, the CypD-dependent mPTP is directly linked to the cellular and synaptic perturbations observed in the pathogenesis of AD. Designing small molecules to block this interaction would lessen the effects of Aβ neurotoxicity. This review summarizes the recent progress on mPTP and its potential therapeutic target for neurodegenerative diseases including AD. This article is part of a Special Issue entitled: Misfolded Proteins, Mitochondrial Dysfunction, and Neurodegenerative Diseases. •Mitochondrial permeability transition pore (mPTP) plays a central role in the development of Alzheimer's disease (AD).•Cyclophilin D (CypD) and reactive oxygen species are also involved in neuronal cell death in AD through mPTP.•CypD-dependent mPTP is directly linked to the cellular and synaptic perturbations in AD.•mPTP as a potential therapeutic target for neurodegenerative diseases including AD.